Stimulated elastase release from human leukocytes: Influence of anti-asthmatic,anti-inflammatory and calcium antagonist drugsin vitro

In the present study the effects of drugs, with different modes of action, on FMLP-stimulated release of elastase from human leukocytes were investigatedin vitro. Anti-asthmatic and anti-allergic drugs were compared to well-known anti-inflammatory and anti-histamine agents. The anti-asthmatic/anti-allergic compounds azelastine, astemizole and oxatomide, and the 5-lipoxygenase inhibitor NDGA, were able to suppress the release of elastase from human leukocytes in concentrations between 10 and 100 μM. NSAIDs such as indomethacin, diclofenac and piroxicam and the glucocorticoids dexamethasone and hydrocortisone showed little or no activity. The histamine H1 antagonists mepyramine and ketotifen and the calcium antagonists verapamil, nifedipine and TMB-8 were also ineffective in suppressing FMLP-induced elastase release. Reduction in elastase release by azelastine, that accumulates in lung tissue during long-term treatment in animals, may contribute to its anti-inflammatory and anti-allergic effects which are thought to be central to its use in asthma therapy.

     

Machen Arbeitsstoffe herzkrank?

Zusammenfassung Herzkreislauf-Erkrankungen sind die wichtigste Todesursache in den Industrieländern. Anders als die Krebsforschung, vernachlässigt die Herzkreislauf-Forschung bei uns toxische Wirkungen weitgehend, abgesehen von den Genussgiften Nikotin, Koffein, Alkohol, einigen Medikamenten und den (bei uns) arbeitsmedizinischen Randproblemen Schwefelkohlenstoff, Nitratester und Kohlenmonoxid. Es sind aber zahlreiche kardiovaskulärtoxische Arbeitsstoffe bekannt: neben den Genannten auch organische Lösemittel, Metalle, Pestizide, Vinylchlorid, polychlorierte Biphenyle, etc. Ebenso sind verschiedene toxische Wirkmechanismen auf das Herzkreislaufsystem bekannt: z. B. langfristige Entstehung von Arteriosklerose, Bluthochdruck, koronaren Herzerkrankungen, Herzmuskelerkrankungen und Herzrhythmusstörungen. Die Vernachlässigung kardiovaskulär-toxischer Wirkungen widerspricht der Logik; bei vielen Herzkreislauf-Erkrankungen ist eine toxische Mitverursachung plausibel; mit einer weiteren Aufdeckung kardiovaskulär-toxischer Wirkungen ist zu rechnen.

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Summary Cardiovascular diseases are the most important cause of mortality in industrialised countries. Contrary to cancer research, cardiovascular research mostly ignores toxic effects, apart from nicotine, caffeine, alcohol, a few pharmaceutical drugs, and the (in our countries) minor workplace problems carbon disulfide, nitrate esters, and carbon monoxide. But many workplace chemicals are known to be harmful to the cardiovascular system: beside the mentioned, also organic solvents, metals, pesticides, vinylchloride, polychlorinated biphenyles, etc. Several toxic mechanisms in the cardiovascular system are already known: e.g., long-term development of atherosclerosis, hypertension, coronary heart disease, cardiomyopathy, and arrhythmia. To neglect cardiovascular toxicity is contrary to logic; for many cardiovascular diseases toxic effects may be constitutive; more of these effects may be seen in the future.

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Résumé Les maladies cardiovasculaires sont les causes de mort les plus fréquentes dans les pays industrialisés. Contrairement à la recherche sur le cancer, la recherche cardiovasculaire chez nous néglige largement les effets toxiques, à part la nicotine, la caféine, l'alcool, quelques médicaments et les problèmes (chez nous) marginaux de médecine du travail tels que le sulfure de carbone, les esters de nitrate et le monoxyde de carbone. Beaucoup de substances rencontrées sur le lieu de travail sont pourtant connues pour être toxiques pour le système cardiovasculaire: celles déjà citées, les solvants organiques, les métaux, les pesticides, le chlorure de vinyl, les biphényles polychlorés, etc. Plusieurs mécanismes d'action toxique sur le système cardiovasculaires sont également connus, par exemple la formation à longue échéance d'artériosclérose, d'hypertension artérielle, de coronopathies, de cardiomyopathies, de troubles du rythme cardiaque. Négliger la toxicité cardiovasculaire est illogique; les effets toxiques pourraient contribuer à la genèse de beaucoup de maladies cardiovasculaires; la découverte d'autres effets toxiques cardiovasculaires est à prévoir.

     

Isokinetic quadriceps training in patients with patellofemoral pain syndrome

The aims of the present investigation were (a) to evaluate the effect of eccentric quadriceps training in patients with unilateral patellofemoral pain and (b) to compare the effect of eccentric and concentric quadriceps training in patients with bilateral patellofemoral pain. Fifteen patients (9 male and 6 female, aged 17–36 years with a mean of 27.5 years) participated in this study. Nine patients had unilateral pain and trained their painful leg eccentrically, while six had bilateral pain and trained one leg eccentrically and the other concentrically. Quadriceps muscle training was performed on a Kin-Com dynamometer at 90°/s and 120°/s angular velocity twice a week for 8 weeks. Before and after the treatment period the thigh muscle torques were measured on the Kin-Com dynamometer at 60°/s, 90°/s, 120°/s and 180°/s for quadriceps and at 60°/s and 180°/s for hamstrings. Nine controls, matched for gender and age with the group with unilateral pain, were tested in the same way on the Kin-Com dynamometer. For functional evaluation a knee score was calculated before training, after 8 weeks of training and at a mean of 3.4 years after completion of the training. After 8 weeks of training and at follow-up times of 1 and 3.4 years the patients were also questioned regarding whether or not they felt improvement from the training programme. To determine the degree of knee pain during the training Borg's pain scale was used. The results showed that, compared with the controls, the patients had a significantly lower knee extensor torque in their painful leg at all velocities measured. The greatest difference was found during eccentric actions. However, in comparison with the controls there were no significant differences in eccent ic and concentric knee flexor torques. After training there was a significant increase particularly in eccentric but also in concentric torque of the knee extensor in the painful leg of the eccentrically trained group. Of the six patients in the bilateral training group there were five who increased their concentric knee extensor torque and three who increased their eccentric torque. There were no significant differences in concentric and eccentric knee flexor torques before and after training in either of the legs in both training groups. The hamstring/quadriceps ratio was significantly higher in the patients' painful leg before training. However, due to increased quadriceps strength the hamstring/quadriceps ratio dropped after training. Patients in both groups reported no pain or mild pain during the training sessions. The eccentrically trained group was significantly improved both after 8 weeks of treatment and at follow-up 3.4 years later as evaluated using the knee score. The bilaterally trained group was significantly improved 3.4 years after completion of the training programme as evaluated using the knee score.     

Growth effects of epidermal growth factor (EGF) and a monoclonal antibody against the EGF receptor on four glioma cell lines

Summary Epidermal growth factor (EGF) has been shown to stimulate DNA synthesis and cell division in normal glia. At least half of malignant human gliomas (MHG) express high levels of the EGF receptor (EGFR), which are above those detected in normal brain. The demonstration that antibodies against the EGFR inhibit the growth of squamous cell carcinoma line A-431, with large numbers of EGFR, in vitro and in vivo raises the possibility that these agents could be used therapeutically against malignant human gliomas either alone or conjugated to other agents. We have measured the growth effects of EGF and an anti-EGFR monoclonal antibody, 528 (Ab-528), on four well-characterized human malignant glioma cell lines, D-263 MG, D-247 MG, U-343 MGa Cl 26, and D-37 MG, with 2.9×10⁴, 1.5×10⁵, 8.6×10⁵ and 1.59×10⁶ EGFRs per cell, respectively. EGF significantly increased cell number in D-263 MG and D-37 MG by 65% and 74%, respectively, had no effect on D-247 MG, and significantly decreased cell number in U-343 MGa Cl 26 by 39%. U-343 MGa Cl 26 growth was inhibited 19% by Ab-528, but Ab-528 had no effect on growth of the other MHG lines. Ab-528 significantly inhibited all EGF-mediated growth effects. These studies demonstrate that, although Ab-528 alone has little antiproliferative activity on MGH, it successfully competes with EGF to reduce the biological effects of EGF-EGFR binding. Therefore, this antibody could potentially be used to target radioisotopes to MHG via the EGFR for diagnosis and therapy.Supported by Grants CA-11898, NS-20023, CA-43722, and the Association for Brain Tumor Research (MHW, PAH)     

Regulatory effects of biophysical strain on rat TMJ discs

Recent studies have revealed that dynamic biomechanical forces can exert antiinflammatory and antiproteolytic effects on fibrocartitage. Whether the effects of mechanical strain also involve stimulation of the insulin-like growth factor (IGF) system and, therefore, of growth and repair of fibrocartilage has yet to be determined. The objective of this in vitro study was to determine if continuous biophysical strain regulates the gene expression of IGF1, IGF2, IGF1 receptor (IGF1R), insulin receptor substrate (IRS1), and IGF-binding proteins (IGFBP) 3 and 5 in cells from the fibrocartilaginous disc of the temporomandibular joint (TMJ). Rat TMJ disc cells were subjected to continuous biophysical strain (3% and 20%) for 4 and 24 h. Subsequently, RNA was extracted and real-time PCR was performed using an iCycler iQ detection system to analyze the gene expression of the IGF system. The gene expression of IGF1, IGF2, IGF1R, IRS1, IGFBP3, and IGFBP5 was significantly (p < 0.05) inhibited when cells were subjected to continuous biophysical strain, as compared to control at both time points. High strain induced a stronger inhibition of these molecules as compared to strain of Low magnitude. In conclusion, continuous biophysical strain seems to downregulate the expression of the IGF system and may, therefore, reduce the potential of fibrocartilage for growth and repair.     

Emerging paradigms of T-cell co-stimulation

The analysis of recent data reveals that T-cell co-stimulation is a hierarchical process with elements of mutual interdependence between individual co-stimulators. The expression and function of co-stimulatory molecules is biased on various T-cell subsets and is dependent on the T-cell differentiation state. The classical paradigm of T-cell co-stimulation by professional antigen-presenting cells has to incorporate the newly recognized concept of T-cell co-stimulation in the interaction with peripheral tissues, such as endothelial or epithelial cells. The two signal paradigm of T-cell co-stimulation is being replaced by a multisignal integration concept of central and peripheral co-stimulation.     

Epidermal growth factor and trefoil factor family 2 synergistically trigger chemotaxis on BEAS-2B cells via different signaling cascades

Injured areas of the respiratory epithelium are subject to rapid repair by the migration of adjacent epithelial cells, a process termed "restitution". Rapid re-epithelialization is promoted by interactions between migrating cells and the extracellular matrix proteins. Furthermore, epidermal growth factor (EGF) as well as trefoil factor family (TFF) peptides are well known regulators of epithelial restitution due to their motogenic effects. Migration of the human bronchial epithelial cell line BEAS-2B in modified Boyden chambers was used as a model system for airway restitution. EGF or recombinant human TFF2 or TFF3 showed mainly chemotactic activity. The motogenic response was strictly dependent upon a haptotactic substrate, but to different degrees. EGF induced phosphorylation of extracellular signal-regulated kinases (ERK) 1/2, c-Jun-N-terminal kinase, p38, Akt, and p70S6K in BEAS-2B cells. Using specific inhibitors, the signaling cascades responsible for the motogenic response were shown to differ drastically when EGF was compared with TFF2. The motogenic effect of TFF2 was previously demonstrated to depend on ERK1/2 and protein kinase C activation; whereas the EGF-triggered motogenic response was completely independent of ERK1/2 activation but sensitive to the inhibition of phosphoinositide 3-kinase, p38, protein kinase C, or nuclear factor kappaB. However, the motogenic effects of EGF and TFF2 are additive. These data suggest that luminal EGF and TFF peptides can act synergistically in the human respiratory epithelium to enhance rapid repair processes in the course of diseases such as asthma.     

Proposed quality control guidelines for antimicrobial susceptibility tests using tilmicosin.

Quality control guidelines for tilmicosin, a novel veterinary-use-only macrolide, were developed in a multi-laboratory study according to established National Committee for Clinical Laboratory Standards (NCCLS) procedures (M23-T2). Tilmicosin was incorporated into Sensititre plates for broth microdilution endpoint testing and into two lots of 15-micrograms disks for Kirby-Bauer agar disk diffusion testing. One common lot and five unique lots of Mueller-Hinton media were used. (Broth was cation adjusted, and agar was supplemented with 5% defibrinated sheep blood.) Bacteria used for reference strains included Pasteurella haemolytica 128K, Pasteurella multocida ATCC 43137, and Staphylococcus aureus ATCC 29213 (microdilution) and ATCC 25923 (disk). Replicate tests were conducted. Disk diffusion and broth microdilution quality control ranges are proposed.     

20q13.2 Amplification in intraductal hyperplasia adjacent to in situ and invasive ductal carcinoma of the breast

The 20q13 region harboring recently described putative oncogenes is frequently amplified in invasive ductal carcinoma (IDC). The aim of this study was to examine the 20q13 copy number in intraduct hyperplasia (IH), atypical duct hyperplasia (ADH), and ductal carcinoma in situ (DCIS) adjacent to IDC. In 5 patients, comparative genomic hybridization (CGH) after laser microdissection revealed 20q13 amplification in four of five cases of IH, in all of three cases of IH with atypia, all five of DCIS, and all five of IDC. Fluorescence in situ hybridization (FISH) confirmed the amplification at 20q13.2 in IH in the two specimens analyzed. The amplification rate, however, was higher in DCIS and IDC. In phenotypically normal ductal epithelium normal values were found for 20q13 copy number by FISH (n=2) and CGH (n=5). Although the number of cases presented here is small, our results suggest that mutations in the 20q13.2 region in IH may be associated with accelerated proliferation and hyperplasia of the ductal epithelium. Progression to DCIS and ICD is accompanied by a further increase in the 20q13.2 copy number. Received: 17 March 1999 / Accepted: 22 June 1999     

An unusual clinical presentation of bilateral schizencephaly

Summary We present a case with a characteristic magnetic resonance image (MRI) of bilateral open-lipped schizencephaly and atypical clinical presentation. The patient is still alive and in good health in her forties, she has never presented seizures, and although the motor dysfunction is well correlated with cerebral lobe involvement, neurobehavioral dysfunction is not proportional to the MR image of the cerebral malformation.

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Un cas inhabituel de schizencéphalie bilatérale

Résumé Nous présentons un cas de schizencéphalie bilatérale ouverte caractérisé par une présentation clinique atypique et une imagerie par résonance magnétique nucléaire caractéristique. La patiente est encore vivante, en bonne santé, à plus de 40 ans, elle n'a jamais présenté de crise comitiale et, bien que les troubles moteurs soient bien corrélés aux altérations cérébrales, les troubles neuro-comportementaux ne sont pas proportionnels aux images IRM de cette malformation cérébrale.